Epstein Barr virus (EBV) is a gamma herpes virus that latently infects greater than 90% of the adult population. Despite a relatively benign course in most carriers, EBV has growth transforming potential and is associated with a number of malignancies, including nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. EBNA1 is a vital EBV latency antigen that maintains the viral episome and is found in all EBV-associated tumors. EBNA1-specific CD8+ T cell immunity is blocked by its glycine-alanine repeat domain, which prevents proteosomal processing for MHC class I. However, our laboratory recently showed that the normal host response to EBNA1 lies in the CD4+ TH1 T cell compartment. TH1 CD4+ T cells are known to be critical for resistance to tumors and viruses in mice. This project will characterize EBNA1-specific CD4+ lymphocytes in several ways. First, we will optimize techniques to detect EBNA1 - specific responses using intracellular cytokine staining and real time PCR and thereby have methods to follow this immune response in patients with EBV-associated malignancies. Second, we will investigate the role of the antigen-presenting cell in the polarization of the CD4+ T cells to TH1 in vivo. We will describe the phenotype of the EBNA1- specific response in blood and tumor infiltrating lymphocytes from patients with EBV-associated Hodgkin's lymphoma and nasopharyngeal carcinoma to determine if EBNA1 immunity is reduced or changed to a TH2 response. Finally, we will learn to expand EBNA1 immunity in T cells from patients with EBV-associated malignancy, including if need be redirect established TH2 responses to TH1. These experiments will set the stage for clinical studies, most likely with dendritic cells pulsed with EBNA1, to manipulate the immune response in patients with EBV- associated malignancy.